Plasma GPC3 and its association with tumor GPC3 expression and clinical outcomes in advanced hepatocellular carcinoma treated with atezolizumab and bevacizumab.

596 Background: Glypican‐3 (GPC3) is a membrane proteoglycan expressed in ~80% of hepatocellular carcinomas (HCC). In addition, GPC3 is cleaved by proteases, shedding its N-terminal fragment into the circulation. While GPC3-targeted therapies are under clinical development, the relationship between tumor GPC3 and plasma GPC3 (pGPC3) remains unclear. Here, we investigated the correlation between tumor GPC3 and pGPC3 and their associations with clinical outcomes in HCC patients. Methods: This study included 186 patients with advanced HCC treated at CHA Bundang Medical Center (2017–2023). Tissue GPC3 levels were assessed by immunohistochemistry (IHC) and RNA-seq, while pGPC3 was assessed using ELISA in 166 patients. Clinical outcomes were investigated in 106 patients treated with first-line atezolizumab plus bevacizumab (atezo/bev). H-score groups were defined as: 0 (negative), 1–100 (low), 101–200 (intermediate), and 201–300 (high). Results: The median IHC extent of GPC3 was 80%, reflecting widespread expression in tumor tissue. The median pGPC3 level was 11.4 pg/mL, with 40.7% of patients undetectable. pGPC3 significantly correlated with H-score (R=0.40, p<0.001) and RNA-seq (R=0.28, p=0.006). pGPC3 positivity (>0 pg/mL) increased proportionally across H-score groups (p<0.001); however, even in the high group (201–300), 25.9% of patients had undetectable pGPC3. pGPC3 was higher in patients with BCLC stage C, PVTT, AFP ≥400 ng/mL and no prior local therapy. High pGPC3 (>10 pg/mL) was associated with shorter progression-free survival (PFS) (3.4 vs 9.4 months, p=0.003), overall survival (OS) (12.3 vs 30.6 months, p<0.001), and lower objective response rates (17.9% vs 47.9%, p=0.001). Time-dependent ROC showed that pGPC3 had a higher predictive accuracy than tumor GPC3 for PFS and OS at both 6- and 12-month time points. In multivariable analysis, high pGPC3 was independently associated with worse PFS (Hazard Ratio [HR]=1.68, 95% Confidence Interval [CI]: 1.06–2.66, p=0.03) and OS (HR=1.93, 95% CI: 1.11–3.36, p=0.02). Conclusions: pGPC3 showed positive correlation with tumor tissue GPC3 and high pGPC3 was associated with poor survival outcomes in patients with advanced HCC treated with atezo/bev.